PROJECT SUMMARY It is estimated that nearly 10% of adults globally are obese and it is a common problem in children. The incidence of obesity continues to grow in the US and in developing nations. There is an urgent need to understand how obesity affects immunity to infections. T cells are a principle cell type responsible for protection against virus infections, and there is evidence from epidemiological studies and in mouse models that obesity reduces immune protection against infections and vaccine efficacy. Our goal is to use a mouse model of virus infection to interrogate how adipose tissue and obesity affect T cell responses to infection. Lymphocytic choriomeningitis virus (LCMV) causes a systemic infection but is resolved within a week by CD8+ T cells. Many of these virus-reactive T cells go on to establish a pool of memory T cells that expedite protection against re-infection. Recently, we discovered that very large frequencies of virus-specific memory T cells reside within adipose tissue. These cells are phenotypically and functionally distinct from memory T cells in lymphoid tissues. Interestingly, diet-induced obesity increased the abundance of these adipose memory T cells, however, immune obese mice developed severe T cell-mediated pathogenesis upon re-infection. The pathogenesis included necrosis of adipose and pancreatic tissues, elevated lipase levels, and reduced levels of circulating calcium. The experiments outlined in this application will allow us to better understand how obesity and adipose tissue interactions affect T cell memory and immune defenses. In Aim1, we will learn how memory T cells develop and are maintained in adipose tissue. In Aim2, we investigate how obesity and adipose cytokines alter memory T cell number, function and distribution. In Aim3, we will determine which T cell effector function causes lethal outcomes during obesity and whether lipase inhibition or calcium supplementation can be used to protect against lethality. These efforts will support our long-term goal to better understand how T cell-adipose tissue interactions worsen outcomes to infection. We plan to eventually translate these findings into therapies for human subjects with weight disorders.